Mitomycins and the corresponding mitosene analogues are well-known examples of reductive alkylating quinones. The reductive alkylation process involves the formation of an alkylating quinone methide species upon reduction of the quinone and elimination of a leaving group. Since tumor cells possess a low reduction potential environment, there is a great deal of interest in reductive alkylating quinones as selective antitumor agents. Thus, a wide range of mitomycin and mitosene derivatives have been prepared in an effort to optimize antitumor activity. All of these derivatives possess the indole ring nucleus, but with a variety of substituents.
Our efforts revealed that benzimidazole-based reductive alkylating agents are also capable of forming an alkylating quinone methide species (See: Skibo, E. B., J. Org. Chem, 1986, 51, 522). Altering the indole nucleus of mitosene to benzimidazole (azamitosene) therefore became important in terms of antitumor agent development.
A problem with reductive alkylating agents arises from the formation of toxic oxygen species when cycling between the quinone and hydroquinone forms of the agent. (See: Doroshow, J. H., Cancer Res., 1983, 43, 460; and Begleiter, A., Cancer Res., 1983, 43, 481). In the case of daunomycin, the iminoquinone derivative of this reductive alkylating agent possesses lower oxygen toxicity than the quinone derivative. (See: Tong et al, J. Med. Chem., 1979, 22, 36). Thus, our efforts also included the preparation of hydrolytically stable iminoazamitosenes and detailed studies of their electrochemistry and oxygen reactivity.